To treat periodontitis, mucoperiosteal flaps are used to obtain access to bone and root surfaces. They are also used for debridement, pocket elimination, management of periodontal defects, implant surgery and in regenerative procedures. During the dissective procedure, the periosteum is usually separated from the alveolar bone proper, particularly in the area of the attached gingiva extending behind the mucogingival junction. A layer of lining cells remains attached to the bone surface, and the rest of the fibrous tissue layer is retained as part of the reflected flap. Many reports show that periodontal surgery stimulates osteoclastic activity with varying amounts of alveolar crest loss, unpredictably resulting in bone dehiscence and tooth loss.
In orthopedic surgery, as well as in periodontal surgery, striking bone remodeling activity occurs adjacent to the site of injury. This reaction has been termed "regional accelerated phenomenon" (RAP). It has been suggested that RAP occurs because osteoclasts (which resorb bone) and osteoblasts (which form new bone) do not exist in sufficient numbers to heal the bone following surgery.
Certain bisphosphonates have been used in the past to inhibit bone resorption. These include: clodronate, pamidronate, etidronate and alendronate. Alendronate is currently marketed in oral form as a treatment for postmenopausal osteoporosis, and others are marketed as systemic treatments of Paget's disease and conditions associated with bone cancers. Many bisphosphonates suffer from a low bioavailability, and in some cases the amount of bisphosphonate which must be delivered in order to produce a biological effect is so high that adverse side effects can occur.
Previously, the bisphosphonate alendronate (4-amino-1-hydroxy-butylidene 1,1,-bisphosphonic acid) was administered intravenously to prevent and treat periodontal disease (See U.S. Pat. No. 5,270,356).
U.S. Pat. No. 5,403,829 discusses the use of bisphosphonates, particularly clodronate, to enhance bone formation after oral or orthopedic surgery. Clodronate was delivered intramuscularly to the test animals.
Yaffe et al., 1995 J. Periodontology 66(11):999-1003 studied the effect of alendronate on alveolar bone resorption following surgery. Alendronate was administered either intravenously or using topical applications. While the intravenous administration was shown to reduce the amount of alveolar bone resorption, alendronate solutions applied topically were not found to be effective in inhibiting bone resorption.
It would be desirable to develop a topical bisphosphonate which can be directly applied to the site of bone injury which would prevent bone resorption, so that widespread systemic administration of bisphosphonates need not be used.